Role of prefrontal cortical dopamine in aggression Abstract Aggression is a complex social behavior that may impose a significant toll on society. Although the mechanisms remain elusive, the prefrontal cortex (PFC) exhibits top-down inhibitory control of aggressive behaviors. However, a fundamental question is how neurons in the PFC control aggression versus normal social interaction and how these neurons are regulated by dopamine (DA), a major neurotransmitter for emotional control. One mechanism through which this may occur is activation of neurons with differential DA receptor expression profiles. Recent studies have demonstrated a segregation of D1R- and D2R-expressing neurons in the PFC. Since D2R antagonists are effective in the treatment of aggressive behaviors, we predict that these divergent D1R- or D2R-expressing neurons are likely endowed with different synaptic connectivity and afferent inputs to enable the execution of distinct regulation in social and aggressive behaviors, respectively. Indeed, our preliminary data indicate that both aggression and normal social interaction induced significant increases in levels of c-fos expression compared with asocial groups in the PFC; but interestingly, episodes of attack significantly increased c-fos expression in D2R-expressing neurons, whereas basal social interaction clearly increased c-fos expression in D1R-expressing neurons in the PFC. Based on these observations, we hypothesize that prefrontal DA regulates social behaviors via differential effects on D1R- and D2R-expressing neurons within PFC circuitry. Specifically, DA promotes basal social interaction through activation of D1R-expressing neurons, but triggers aggressive behavior by activating D2R-expressing neurons. We will use Cre-dependent transgenic mice combined with pharmacogenetics to test this hypothesis. In Aim 1, we will identify the roles of D1R- and D2R-containing PFC neurons in social and aggressive behaviors, and then characterize their neuronal and synaptic properties that are differentially affected by social interaction and aggression, respectively. In Aim 2, we will determine whether pharmacogenetically manipulating the functionality of D1R- and D2R-expressing cells within the PFC is capable of promoting social interaction or controlling aggressive behavior. This proposal will determine the role of the PFC in aggression control and dissect the specific effects of DA receptor subtypes on social behaviors in a cell-type specific manner. Our study will bridge a gap in the literature given that we aim to offer causative evidence of the ?social neural circuit? containing prefrontal D1R- and D2R-expressing neurons in regular social interaction and escalated aggression.